All posts in Ampligen

Ampligen has been in the FDA pipeline for so many years that it almost seems like a mirage at this point. The ME/CFS community has been praying, hoping, believing that Ampligen will be its first FDA approved drug for over twenty years. For a lot of people that hope may have died, but the drug has gotten new life recently.

A Little History

If Ampligen has failed to gain approval at least it and the company have been entertaining. Ironically, given its long and rather harrowing path through the FDA, Ampligen’s first use in an ME/CFS patient was prompted by none other than the FDA. After an ME/CFS patient with culture evidence of HHV-6 infection significantly improved clinical trials began.

Ampligen has trod a difficult path at the FDA over the past twenty years.

Problems occurred early on, however, when Hemispherx Biopharma, the drug’s maker, cut the trial duration in half, and ME/CFS patients sued at one point to get access to the drug. The early Ampligen trials in chronic fatigue syndrome ultimately sparked the publication of a hilarious novel by Floyd Skloot, Patient 002.

The company came under fire early. In the early 1990’s CAA President Kim Kenney (McCleary) said “Ampligen is a good drug in the wrong hands”. Daniel Hoth, then head of the National Institutes of Health’s AIDS drug program, went further when he told the Wall Street journal that “no professional drug company with any degree of professionalism would ever develop Ampligen the way it was developed by HEM.”

Difficult Path

Hemispherx Biopharma, though, has never had an easy time of it. In what surely must be a record for frustration for a drug company, Ampligen was moved to a different section of the FDA four times; each move eliciting a new review and different findings.

The FDA panel’s rejection of Ampligen in 2013 provided more head-shaking moments when two ME/CFS experts unexpectedly voted against it, and several non- ME/CFS experts (citing the community’s urgent needs) voted to approve it.

Hemispherx felt blindsided at the hearing by safety issues it been told had been addressed years ago, and which it didn’t feel it was given adequate time to respond to. (Since then FDA officials have said safety is not a major issue). It’s no wonder the company has felt at times that the deck has been stacked against them.

With the FDA asking for large drug trials that HB lacked the funds to produce, Ampligen finally seemed to be dead, but a new push to understand ME/CFS at the NIH may be producing a sea change for the drug.

Patients Push FDA To Approve Drug

More than anyone, ME/CFS patients know of the cost of having no FDA approved drugs. Patient outcry at the FDA denial of Ampligen in 2013 – including an 11-day hunger strike by patient Robert Miller, 5,000 signatures petitioning the FDA to reconsider, and thousands of emails from patients and Congresspeople flooding the FDA – prompted the FDA to conduct a Drug Development Workshop in 2014 and publish guidance for the industry on ME/CFS drug development.

The FDA’s effort to spur drug company interest in ME/CFS appears to have failed, however, leaving Ampligen still the only drug candidate within short-term reach of drug approval for a disease that the FDA acknowledges urgently needs approved treatments.

With NIH director Francis Collin’s commitment to reinvigorate chronic fatigue syndrome (ME/CFS) research and mentioning the possibility of an NIH funded Ampligen trial, it’s time to take another look at the “first” drug for ME/CFS.

Renewal

Thomas Equels has vowed to make the company attractive to investors

The Board of Hemispherx Biopharma (HB) responded to the new climate of interest by replacing its longtime President and CEO, William Carter, with its Chief Financial Officer, Thomas Equels. Equels vowed to whip company into better financial shape in order to attract investors who could help get Ampligen FDA approval. FDA approval of Ampligen, he declared was HB’s number one priority, and he would work arm in arm with the FDA to achieve that.

Ampligen

Ampligen is an immunomodulator that targets a portion of the immune system that fights viruses. Ampligen’s producer, Hemispherx Biopharma, was surely cheered by the assignment of a major NIH study to a neuroinfectious disease specialist, Dr. Avindra Nath.

Ampligen’s use in ME/CFS is predicated on the idea that viruses and/or immune issues are playing havoc in the disease. Ampligen is a toll -like receptor three (TLR-3) inducer. The receptor it binds to are found on antigen presenting cells such as dendritic cells that have been exposed to pathogens.

The binding of the receptor activates hundreds of genes in a cell. The side effects from most TLR inducing drugs limits their effectiveness, but Ampligen is unique among these drugs in that it does not cause cells to produce large amounts of pro-inflammatory cytokines.

Efficacy

Reports of Ampligen’s ability to dramatically improve the health of some people with ME/CFS abound.

The 90,000 doses given safely through Hemispherx Biopharma’s compassionate care program to ME/CFS patients by a handful of doctors in the U.S. have produced some startling stories of improvement and recovery.

Ampligen’s success stories attest to the drugs effectiveness in some people

Anita Patton, Mary Schweitzer, Bob Miller and Kelvin Lord have all documented their Ampligen success stories. Several experienced significant improvement while on it only to relapse while off it. Anita Patton essentially went from bed bound to normal functioning on Ampligen, back to being bed bound off of it, and then again to normal functioning when back on the drug.

Kelvin Lord’s story was perhaps most representative. He’s provided the most complete (and funniest) review of an ME/CFS patient’s experience with Ampligen in a series of blogs titled “The Ampligen Chronicles”. Faced with rapidly deteriorating health, Ampligen was Kelvin Lord’s last shot at health. To his surprise and delight it worked.

It didn’t return this businessman, flight instructor, skier and parasailor to complete health, but Kelvin did progress from being barely able to walk to be able to work 6 hours and do 45 minutes of resistance exercises a day. His brain fog, orthostatic intolerance, canker sores and extreme fatigue disappeared. He was back to being a productive human being for a major part of his day – a huge jump. (Read about it here.) Going from bed bound to productive is probably a bigger jump, it should be noted, than most FDA approved drugs provide.

(Find other stories in Health Rising’s Ampligen Resource Page.)

Of course, examples of Ampligen’s lack of efficacy can be found as well, but this is to be expected given the heterogeneous nature of ME/CFS. Until the subsets in ME/CFS can be targeted with treatments unique to them, treatment efficacy even for most effective treatments, is probably going to be fairly low – perhaps around the 30-40% mark found in Ampligen.

Studies

“The drug has not received a marketing approval despite the lack of proven efficacious agents in the treatment of this disease that can be severely debilitating and is estimated to effect over one million persons in the US.” The author

W.M. Mitchell, a Vanderbilt pathologist and HB Board member, recently published an overview of Ampligen in a pharmaceutical journal. (Mitchell recently co-authored a study which reported finding a significantly more accurate blood test for prostate cancer.)

Thirteen Ampligen trails have been done over the past 20 years or so. Nine occurred in severely ill prior fatigue syndrome patients; three of these were large multisite trials and five were open label trials measuring safety and efficacy. All told over 830 different ME/CFS patients have received over 90,000 doses of Ampligen. Most of the patients in the studies had been ill for at least 6-9 years.

The results of the trials have been positive. The first 92 person trial found significant increases in Karnofsky performance scores (p<.001), quality of life, exercise tolerance and oxygen utilization during exercise. Ampligen receiving patients also used significantly less drugs to alleviate their symptoms than placebo receiving patients.

The number of patients seeking emergency room care demonstrated how severely ill the patients in the study were, and how helpful Ampligen might be if it were available. Ampligen cut the number of patients visiting the emergency room in half (from 15% to <8%). The placebo patients stayed an average of eight days at the hospital, while the Ampligen receiving patients stayed an average of less than three days.

(In how many diseases would 15% of the patients in the clinical trial spend an average of 8 days at a hospital over the duration of the trial? This was a very severely ill cohort.)

The primary endpoint of next 234 person trial was exercise intolerance. The results, which barely reached the minimum standard of significance (p< .05/ p<.048), indicated that exercise tolerance increased on average about 22%. Overall Ampligen improved VO2 max results on the exercise test by 5.5%, and Ampligen receiving patients were able to stay on the treadmill for about nine minutes longer than placebo receiving patients.

Further analyses found 3 cohorts of patients with regards to exercise tolerance; high responders, mild responders and no responders. Overall patients on the drug improved significantly more than patients given placebo (p<.001).

As in the first study, hospital visits were significantly reduced in the Ampligen receiving cohort and Karnofsky performance scores were significantly increased.

The two clinical studies suggest that 30-40% of people with severe ME/CFS can be expected to get “clinical benefit” from Ampligen.

The trials were mostly successful, but did have their problems. The company stopped the first trial early and then modified the second trial in midstream. Even though the second trial was successful a great deal of discussion at the FDA hearing involved why the trial was modified. Records could have better kept as well.

From the ME/CFS communities perspective, though, the success of both trials was paramount. Many felt the lapses should have overlooked given the urgent need for treatments in such a large and often disabling disease. Many also felt that the positive testimony by doctors who had been using the drug for years should have been given more weight.

Conclusion

While there were some problems with the trials the drug did meet several important endpoints including increasing time on a treadmill and increased oxygen utilization. It should be noted that Ampligen has tried to move the needle on probably the most difficult factor of all to budge in ME/CFS: oxygen utilization during exercise.

Any drug providing clinical benefit to 30-40% of a population which has no approved drugs should be a slam dunk. (Less effective drugs have been readily approved in other illnesses). Hopefully, with new leadership, Hemispherx’s twenty plus year journey to bring Ampligen to market will end successfully, and the ME/CFS community will finally get its first drug approved.

It seems like Hemispherx Biopharma – the maker of Ampligen – has been the under the gun for years. Last year it settled a 2012 class action lawsuit alleging it made false and misleading claims about Ampligen. It endured another lawsuit in 2009 for more alleged federal securities violations. Last year it was called “a penny-stock firm with a penchant for hype” by Damien Garde at Fierce Biotech.

Hemispherx Biopharma’s financial resources have declined recently

According to Investor Wired Hemipsherx’s net loss including non-cash effects, averaged about $12 million or $(0.05) a share in the first nine months of the last two years.With regards to cash, cash equivalents and marketable securities the company lost about $4 million in the first nine months of 2015 ($16,108,000 – $12,375,000).

The news has not been all bad, though. Hemispherx Biopharma was rated the ninth best performing health care stock of 2012. Citing Hemispherx’s ability to achieve additional patent protection for Ampligen in Europe through 2029, Investor Wired put Hemispherx Biopharma on its “Biotech Stocks to Watch List” at the end of last year. It’s all more of the roller-coaster for Ampligen and Hemispherx Biopharma.

The fact that Ampligen is even still around may be something of a small miracle. It’s hard to envision a more difficult drug pathway than for a small drug company producing a drug for a controversial disease like ME/CFS.

It’s a telling sign of drug company wariness towards ME/CFS that decades after Ampligen was introduced, it’s still the only drug to go through the FDA approval process for the disease, and no other drugs are in sight. Until FDA approves the first medicine for ME/CFS, no significant investment in this disease will likely come from the pharma industry. Ampligen represents an important logjam in ME/CFS treatment that has to be solved.

For all the difficulty surrounding Hemispherx, it should be noted that the company managed to keep Ampligen alive long enough to hopefully take advantage of the changed landscape for ME/CFS.

Change at the Top

A new era for chronic fatigue syndrome (ME/CFS) appears to be dawning at the NIH. With Francis Collins, the head of the NIH, taking the lead in the fight to understand and treat ME/CFS, a window of opportunity has opened for Ampligen.

Equels declared that Ampligen is Hemispherx’s number one priority

Hemispherx Biopharma’s first move to capitalize on that opportunity was to fire its long time CEO and Chairman, William Carter (and two of his relatives) and elevate Thomas Equels, former Chief Financial Officer and Executive Vice Chairman to the Presidency.

Stating that it was re-examining its fundamental priorities, Hemispherx Biopharma’s (HB’s) board pledged it would implement a “strong financial austerity plan”. (In 2014, Carter made $2,364,874 including about $2,000,000 in cash and a $894,000 bonus.) Equels was given a mandate to “strengthen internal controls, achieve enhanced governance, and create an environment for greater stockholder value.” Equels was brought in, in other words, to institute a new era of efficiency and productivity in order to appeal to investors.

In an interview Equels stated that “commitment, integrity and cooperation” were to be the new bylines for Hemispherx. He made it clear – in fact, he repeatedly emphasized – that Hemispherx Biopharma’s number one goal was getting FDA approval for Ampligen for chronic fatigue syndrome (ME/CFS). To that end, Hemispherx was developing an “overarching strategy” to pull in public and private investors to move the drug forward. Acknowledging that Hemispherx’s resources were limited at this point, he said he’d be pulling the plug on all non-priority activities.

That overarching strategy includes fixing Hemispherx’s strained relationship with the FDA. There’s been no love lost between the FDA and Hemispherx Biopharma. Several advocates told me they held their breath whenever the sometimes fiery Carter spoke at the FDA hearing. Some felt Hemispherx was treated unduly harshly, and not given the opportunity to respond when safety issues the company thought were resolved came to the fore.

Can Equels finally bring Ampligen across the finish line?

The FDA, however, acknowledges that ME/CFS community urgently needs drug options, and FDA officials have said that the safety issues for the drug have been resolved. Some advocates that have met with them believe they are eager to move forward on ME/CFS.

Equels said he’d met with Janet Woodcock at the FDA to understand where the FDA sees the gaps. He pledged Hemispherx would be there “arms locked with FDA officials” to do what was necessary to move the drug forward. Hemispherx officials also apparently quickly talked with NINDS chief Dr. Koroshetz not long after NIH Director Collins announced the NIH would reinvigorate ME/CFS research.

At the end of the day, Equels said, we have a proven therapy – it’s about bringing it across the finish line.

The Great Room

We were in the ‘Great room’ and it was a great room; an impressive room able to seat several hundred people with large screens covering the sides of one wall so that everybody had a clear view of what was going on. With the FDA often following FDA Advisory Committee recommendations this was where many drugs got approved or not and it felt like it.

The meeting starting out with the FDA rep emphasizing that they ‘got it’; that they understood chronic fatigue syndrome is a serious and sometimes devastating disorder that vitally needs treatment options. Announcing that they were both ‘delighted’ and ‘overwhelmed’ by the 750 testimonials from ME/CFS patients, their servers promptly crashed under the weight of the large online crowd watching the proceedings.

One had the feeling they weren’t used to this level of patient participation.

Just two days prior to the hearing, the FDA made public a highly critical 220 page document outlining the FDA’s concerns on the safety and efficacy data. Hemispherx employees, however, appeared confident they could answer the FDA’s queries.

The Meeting

Hemispherx presented first with its President Dr. Carter flashing Dr. Klimas’ famous quote that she’d rather have HIV than chronic fatigue syndrome and emphasizing that ME/CFS can be life-threatening and is as debilitating as multiple sclerosis, rheumatoid arthritis and lupus.

Safety

A good part of Dr. Carter’s presentation was focused on safety. The FDA’s background information and questions posted just two days earlier had made it clear safety was going to be a major issue; something that clearly flabbergasted Dr. Carter, who noted at one point, that it was not until this year that substantial safety issues had been raised.

One problem Hemispherx faced was that Ampligen is not just a new drug; it’s (a) a drug that affects the complex and powerful immune system, (b) it’s the first of a new class of immune drugs to get this far at the FDA, and (c)some other drugs in this class have had substantial safety issues. The FDA noted that autopsied rodents given Ampligen possibly indicated signs an overheated inflammatory response and they posed questions about the reliability of the safety data.

Stating that Hemispherx had ‘irrefutable evidence’ the drug was not sparking a strong inflammatory response , Carter laid out why. The chemical structure of the drug was distinctly different from the other drugs in its class that had safety concerns. In contrast to those drugs Ampligen quickly metabolized into natural molecules indicating it was giving the immune system powerful but transient nudges – hardly the type of activity that would promote a sustained inflammatory response.

Hemispherx argued that Ampligen’s chemical makeup, it’s quick metabolism in the body and years of clinical data indicated that Ampligen was safe.

The rodent data was simply irrelevant ; unlike humans rodents were slow metabolizers of the drug – which meant the drug sat around in their systems for long periods of time – a danger not faced by humans. Only primates, Dr. Carter asserted, were acceptable test animals for this drug.

Plus 95,000 doses of the drug had been given safely since 1997. Whatever issues FDA had with the original study data, dating back 20 years in one case, subsequent use had shown the drug to be safe. Hemispherx’s 174 safety reports indicated the drug was safe, the drug was being safely used outside the country, no evidence of autoimmune illnesses had ever been reported and with some irritation Carter stated the drug’s safety concerns had been dealt with 18 years ago. Carter also tried to allay cancer concerns by noting Ampligen’s anti-cancer effects were currently being studied at academic centers.

Hemispherx’s chief researcher, Dr. Strayer reported that the no evidence of the FDA’s chief concern, an autoimmune response, had ever been reported and then examined the case of one participant with transient liver problems (another FDA concern) who’s health ended up improving greatly on the drug.

Indeed, the study data indicated the drug appeared to be safe with only minor symptoms (eg flu-like issues, nauseas, abdominal issues)appearing significantly more commonly in Ampligen treated compared to placebo treated patients. The FDA, though, was most interested in the outliers; the few patients who reported severe illnesses while on Ampligen even if they couldn’t be statistically traced to Ampligen.

Efficacy

Lecturing a bit, Carter moved on to assert the FDA had not done the proper type of analyses in their background review. He noted that the drug’s five moves from division to division in the FDA, the company been given different instructions from each. Hemispherx would also refute the FDA’s assertion they had not prepared a statistical plan until after a study was done.

Ampligen’s ability to raise endurance levels, one of the other most difficult things to achieve in this disorder, suggested the drug was hitting core features of the disease.

(This will be a central theme for the FDA; researchers are not ‘allowed’ to examine data later and then highlight what works; they are expected to devise a plan of attack and then stick to it. Hemispherx will argue that they did this and the FDA will argue that they didn’t.)

Following close on Dr. Carter’s heels Dr. Lucinda Bateman told the panel her clinic had been involved in some 30 drug trials for chronic fatigue syndrome and fibromyalgia. Emphasizing the community’s needs for good treatment options, she reported that available treatments tended to be poorly tolerated and generally had modest or no benefits. She posted a report from Dr. Lapp, a long time Ampligen provider, that he’d seen from modest to remarkable results in his patients on Ampligen and had seen no serious side effects .

In response to a question,Dr. Batemen noted that the chief endpoint in the trial, increasing endurance, was a particularly difficult thing to achieve in chronic fatigue syndrome as endurance was one of the last things to improve as patients got better.

Dr. Strayer showed that Ampligen increases endurance much more than the five other drugs approved to do that in other diseases had done, that it significantly increases functionality (average Karnofsky score increases from 50-60) and it allows patients to reduce the use of potentially damaging drugs.

Declaring that I am not a statistic, Bob Miller ended Hemispherx’s presentation with a powerful, personal review of the drug’s promise.

Hemispherx felt the treadmill endurance test results would be both pivotal to their case and difficult for the panel to understand and brought along an expert, Dr. Chris Snell of the Pacific Fatigue Lab, to answer questions. The panel, however, got swept up in other issues.

FDA Presentation

The FDA presentation was unremittingly critical. Using chart after chart, they pointed out irregularities in the data and noted that several times the company changed course in midstream. At one point, for instance, Hemispherx stopped its 1991 trial at 24 weeks instead of continuing it for a year as they’d promised. Another time the company started a trial, recognized that the exercise protocols were too harsh and wiping out the patients, then revised it and eliminated the first 7 patients from the final data set. That seemed to make sense, but every change bothered the FDA and considerable discussion ensued about the significance of those 7 patients.

Hemispherx evoked surprise at the FDA’s recent emphasis on safety data. The Agency was highly critical of what they felt were lapses in the data.

The FDA said that 41% of the people listed as responders no longer could be categorized as such as they continued on the drug in the post-trial cost-recovery period. (Most of the original participants in the trial continued on with the drug after the trial was over – itself a strong commendation for the drug. ). They stated that most of the statistical significance came from just a few patients who improved remarkably on the drug and from patients on placebo who fell apart.

Safety turned out to be a huge issue and the FDA brought up numerous small irregularities; an lupus flare reported for a patient although people with lupus were supposed to be excluded from study, abnormal liver tests in the raw data that didn’t show up in the final report, different numbers for patients who discontinued the study…

The FDA clearly took great affront at these irregularities; it wasn’t necessarily that they altered the results…it was that they were there in the first place. There was no doubt that this was a data set with problems and if you were watching Hemispherx’s stock you would have seen it rise after Hemispherx’s presentation and then plummet after the FDA’s. Hemispherx would have to answer for them in the discussion period to follow. After lunch they appeared ready to do so.

In the end few disagreed that the data indicated that Ampligen was effective at least a subset of patients. The disagreement was whether Hemispherx should be allowed to move forward at that point or whether new studies should be done to target that subset.

Log Transformation

To “log transform” or not to was one of the major issues the FDA raised in their background report; the fact that log untransformed data had shown that Ampligen had a significantly positive benefit while log transformed data indicated the drug (almost did but) didn’t have that effect.

This technical question would dog Hemispherx throughout the hearing; and they would ultimately answer it but one had the feel that it was too late…that the damage had been done. Hemispherx’s statistician, with years of FDA experience under his belt, showed instructions from the FDA stating that log transformation should not be used unless necessary because it could skew the data, and then

The FDA officials were focused on something else, though, when and why Hemispherx decided to log transform or not the data. The big question was whether Hemispherx saw the data before it decided whether or not to transform the data. The statistician appeared to argue that Hemispherx had to check the variance to determine if transformation was warranted but in the end stated the biostatistician who prepared the data was no longer with the company and they didn’t know. That was a huge blow…

Never mind that Hemispherx had demonstrated that the log transformation data was not warranted or that non transformed data was appropriate …the FDA was mostly interested in whether the biostatistician had ‘followed the rules’. It was a bizarre thing as a patient to watch a drug that could help ill people be held up on procedural issues but there it was.

Discussion Period

This is how the FDA approves drugs? More impromptu debate than rigorous analysis the discussion session kind of flowed along from topic to topic with a pro-FDA moderator calling the shots. In fact, an actual debate, with each side arguing pro’s and con’s of each issue would have been much better.

The FDA’s sloppy and rather ad hoc process often felt hurried and did not inspire confidence

Instead of issues being drawn up, presented on the screens and then discussed in an organized manner with each side given equal time, the conversation lurched from topic to topic with the Hemispherx reps being frustrated spectators too many times.

After lunch, Hemispherx had appeared confident even after the morning pummeling they’d taken from the FDA team. They felt they had answers to the FDA’s concerns but after the meeting, several members of the team felt they simply were not provided the opportunity to produce them. The moderator did call on Hemispherx several times but, for the most part, the FDA personnel to held the floor.

The short early discussion period clearly left many questions hanging at a time when the issues were fresh in the reviewers minds but the later discussion period felt hurried as well.

Given the ad hoc nature of the discussion period drugs companies must shake in their boots and investors must tremble when they approach these meetings. Then again, this is an FDA that gives companies 220 pages of background materials and a list of questions to be answered two days before the meeting. The FDA team clearly has the upper hand in these hearings and that’s apparently how they want it.

Process vs Result

The hearing was largely a contest between those focused on process and those focused on the results. The FDA stated months ago that changes in protocols as studies were underway meant the study was now a hypothesis gathering expedition not a validation study. If Hemispherx found out their exercise protocols were too harsh they should have stopped the study , redo their protocols, cleared them with the FDA, enrolled another group of patients and then redo the study. That’s not a process a small drug company will find easy to accomplish.

Hemispherx acknowledged that yes, at times, we had to change things – but when we did, that data showed this drug helps ME/CFS patients. Given the needs of this community we think that should be enough.

Indeed, the needs of the community loomed large in the minds of several panel members who stated that, however irregular the study follow through, they felt Hemispherx showed that the drug helps patients and that was the paramount issue for them.

Several of those who voted against the drug also agreed that Hemispherx did show efficacy at least for a subset of patients but they wanted standard protocols followed and felt there were too many irregularities with the data. They encouraged Hemispherx to do another study.

The FDA released its background report and its list of committee members and, if you want to compare the two, the Agency was even-handed; the report was highly critical and the committee members they picked boded well for Ampligen chances..

REPORT

Harshly Critical Analysis

We knew FDA Advisory Meetings can be intense, rough environments. With the FDA background report on Ampligen you can count that as confirmed. This is not going to be easy for Hemispherx..

The FDA analysis of the Ampligen trials, focusing on methodological issues, mistakes and what it believes are inadequate efficacy and safety data does not, on the face of it, appear to bode well for Ampligen and the market agreed with the stock shaving off half its value the day the report was released.

FDA reports do tend to highlight negatives, not positives which makes sense given the way the meetings are set up; the sponsoring drug company presents its data in its best light, then the FDA does its best to poke holes in it, and then the independent review committee decides.

In the meantime be prepared for a difficult hearing. These FDA Advisory hearings have been described as ‘blood baths’ from which few companies and drugs escape unscathed.

Background

A harsh FDA report presented two days before the meeting did not bode well for Ampligen

The long and rather tattered history of Ampligen at the FDA since 1988 is outlined. The first interagency transfer to a new department occurred in 1992. The long gap between the first proof of concept trial (1990-1991) and the confirmatory trial (1998-2004) probably demonstrated how difficult it was for Hemispherx to raise the money needed to carry out the second trial.

Ampligen’s New Drug Application (NDA) submitted on Oct, 2007 was refused filing because it was missing study reports, ECG and laboratory data, case report forms, ‘dose ranging’, ‘inconsistent statistical plans’, clinical pharmacology data, carcinogenicity data andhad database discrepancies. This was a long list but Hemispherx fixed some of the problems and explained others, and in the first third of 2008 quickly resubmitted the application and it was allowed to move forward.

“Your two main studies (AMP-502 and AMP-516) do not provide adequate evidence of effectiveness or safety.”

In 2012, after being moved to another branch of the FDA, Hemispherx requested to be allowed to re-analyze the data from the second, larger, confirmatory trial. The agency was leery about this approach stating “It would be unusual for this type of data to provide adequate evidence of efficacy.” but allowed the process to continue forward stating the efficacy issues would be addressed at the final review..

Two Trials

The FDA will be relying on evidence from two trials; AMP-502 and AMP-516. (The agency is, unfortunately, not using confirmatory data generated from patients who continued on the drug after the trial because that data was not placebo-controlled.)

Problems had occurred. After finding that the original exercise protocol was too difficult, however, Hemispherx changed the protocol and eliminated the first seven patients from the analysis. ( If those patients are included in the analysis the significantly positive effects disappeared. )

The trial was originally supposed to last for a year but after an interim analysis it was stopped after 24 weeks. The FDA drew attention to the fact that the statistical analysis plan was written and dated 16 years after the completion of the study and later noted ‘multiple protocol violations’ including patients restarting their other medications during the trial had occurred.

Second Trial (1998-2004) – The second larger trial (516), designed to confirm the first trial’s results, failed to show significant increases in self-reported functioning or ETT. Recently Hemispherx re-analyzed the data using patients with lower disease duration (1-10 years) and dichotomous branching techniques and received significantly positive ETT results but still no significant changes in self-reported functionality, daily living, SF-36 or symptom scores.

Hemispherx found that the percent of patients reaching 25% and 50% increases from baseline was significantly increased in patients receiving Ampligen and that patients with lower duration illness (<10 years) were more likely to benefit. Despite reports in the literature that lower duration patients (< 2 years) do tend to respond better the FDA found ‘no scientific rationale’ for the lower duration analysis and advised caution in interpreting them.

Several issues were reported including using median KPS values for some patients and minimum median values for others. Hemispherx also chose to use any response (ie the best response recorded) during the duration of the trial for its endpoint instead of set responses at the end of the trial.

The re-analysis was helpful but the FDA questioned whether these types of re-analyses are suitable for determining efficacy suggesting they are better suited for ‘hypothesis testing’.

Due to the nature of analyses conducted after data unblinding, the Agency generally considers post-hoc analyses to be hypothesis generating rather than forming the primary basis of efficacy for an application.

Hemispherx was caught in the first study with an exercise protocol that was apparently wiping the participants out. In the second , larger ‘confirmatory’ study Hemispherx had to analyze the results differently to get positive results in the exercise testing but not significantly positive results in self-report tests. Changes in protocols and analysis are often red flags to reviewers and questions were raised why a protocol and analysis would work in one trial and not the other.

It was rough stuff but a Hemispherx rep appeared unflustered and confident that the company was ready to respond to the FDA’s report.

Tough Subject – With its subsets and its vague definition, ME/CFS is a difficult field to test any drug in, and drugs that practitioners say have positive results in some patients have failed to achieve them in placebo-controlled trials. If the disorder is larded with subsets then the results of any major trial of a drug that works probably should appear like Hemispherx’s did; that is, it should have weakly significant results because of the patients in the trial who have a different type of disorder altogether. We should also know of people who had excellent results (we do) and doctors who prescribe the medication to targeted patients should have good results (they do).

Subsets will inevitably complicate matters in any clinical trial for chronic fatigue syndrome (ME/CFS) as its defined now

The FDA must realize that it’s facing an unusual challenge in a disorder that is so poorly defined. The background report did not take into account the possibility of subsets watering down the study results but the Committee is made of several members who are well aware of this problem. Dr. Unger of the CDC, for instance, has publicly stated she is sure this is true and is engaged in a study that should help ferret them out.

Indeed a recent analysis suggested the subset problem meant Hemispherx started its trial with one of its hands tied behind its back. Throw in the fact that it’s a small company with limited resources and you probably get what we see; midstream changes that attempt to account for new information and re-analyses to target possible subgroups.

Ampligen’s trials had no way to account for this meta-population problem beyond looking for interesting trends within the data set. And that is what they did… No one seems to know what an appropriate biomarker for the general CFS population is, but the FDA is holding Ampligen up to an unrealistic standard nonetheless. In the end, HEB did find statistical support that Ampligen provides a biologically meaningful impact on the lives of at least some patients with CFS.

The problems facing Ampligen-or any putative therapy for CFS for that matter, is that the underlying cause(s) are unknown. As a result, there are quite possibly distinct sub-groups within any potential CFS study population with markedly distinct pathophysiologies, and hence

Safety

Hemispherx has reported that tens of thousands of doses of Ampligen have been given without issue but the FDA will rely on the results from ‘only’ 567 patients of which ‘controlled data’ are available for only 162. The FDA stated that for drugs intended for long-term treatment they would like at least 1,500 people exposed to the drug for short term periods and 100 for over a year.

Here, too, the FDA cited numerous issues including serious adverse events not reported, marked laboratory abnormalities not reported, miscoding of adverse events and reasons for patient discontinuation of the trial and incomplete/misleading data presentation. Some serious adverse events that resulted in hospitalization were not reported. The discrepancies were enough for the FDA to call into question the data from all the trials.

On the other hand, the side effects that showed up more in patients receiving Ampligen (flu-like symptom, chills, vasodilatation, shortness of breath ) were not particularly significant. Other more serious side effects did occur but not more significantly in patients receiving Ampligen but the Agency expressed concerns about them.

Overall, the Agency has concerns regarding the reliability of the safety database for Ampligen, based upon lack of appropriate documentation and reporting. While review of the safety database for Ampligen suggests that the drug induces a systemic inflammatory reaction with a number of serious events of concern, the lack of reliable reporting prevents any accurate assessment of frequency. The key safety issue for discussion at the advisory committee meeting is whether conclusions can be drawn from the data as it stands …

Hemispherx will explain why the safety data is sufficient and why oversights, omissions, etc. occurred and why they shouldn’t bear negatively on the review.

COMMITTEE MAKEUP – the Good News

Taking the committee makeup into account one analyst predicted a close but positive vote. At least six people have history with chronic fatigue syndrome and I would be very surprised if Komaroff, Marshall weren’t strong yes votes and the others strongly leaning towards yes. If those six vote yes they’re two votes away from a tie vote and three from a majority vote. For me, I think Marshall can be very persuasive once he gets going J.

The harsh FDA report was produced by statisticians with little knowledge of the disorder but the FDA also produced a committee with a core of members with extensive knowledge of ME/CFS. The Committee vote is the key. Will Hemispherx and the patient advocates be able to convince the committee members to overlook a harsh FDA report? We’ll see.

The vote will come at the end of the day. The committee members will be asked to vote all at once so that the members are not influenced by the others votes.

The FDA will take everything into account and release its decision on Feb 2nd. They could approve the drug outright (not likely to happen), approve it with conditions, ask for more studies or just slam the door on the drug.

Decades of hope and work for Ampligen, still the only drug ever produced for CFS, will culminate on Dec 20th.

by Cort Johnson

Ampligen’s time is finally here. Twenty years of effort and hope will culminate on the early evening of Dec 20th, when, following an all-day hearing, an FDA Advisory committee will determine Ampligen’s fate. Palms will be sweating and hearts will be pounding that evening as patients, physicians and their supporters and researchers with decades of work on the line await what will be a momentous decision.

Produced by Hemispherx Biopharma, Ampligen is and has been the only drug under development for chronic fatigue syndrome for over twenty years. No other drugs are waiting in the wings and no other companies appear interested in putting years of effort and millions of dollars into producing or even testing a drug for this disorder.

It’ll all come down to 6-10 or so independent ‘experts’ opinions on whether this drug is safe, effective and worth putting on the market.

Prior to the big decision we’ll see presentations from Hemispherx, the FDA and ME/CFS patients. Dr. Bateman, Dr. Snell and Hemipherx representatives will present for Ampligen.

LOCATION: Open to the Public

Anybody can come and we hope as many people as possible come and if they wish, give testimony. Patient Testimony will be given in 3-minute slots from approximate 1pm to 2:30

Hemispherx is likely to face tough questioning at the FDA Advisory Committee meeting for Ampligen

TOUGH ENVIRONMENT

According to someone who’s been there, FDA Advisory Hearings tend to be in-your-face type affairs in which tough questions and a critical attitude are the norm. If Hemispherx is getting whacked around at the hearing don’t attach too much significance to it; every pharmaceutical company gets hammered at these hearings – even those that get their drugs approved.

My understanding is that there will be two presentations; the FDA will present its interpretation of the data and Hermispherx with Dr. Bateman, Dr. Snell and its own raft of professionals will present its case. The FDA Advisory Board, made up mostly of rheumatologists will pepper each group with questions and come to a decision on three questions.

Does Ampligen work ( efficacy)?

Is Ampligen safe?

Do Ampligen’s benefits outweigh its risks?

Each member will answer each of these questions live and we’ll get their decision in public that day. From there the FDA will take their reports into account and submit their final ruling on Feb 3rd, 2013. They almost always follow the decisions of the Advisory Board.

Still Some Unknowns

There’s still quite a bit about this meeting that we don’t know and that the FDA probably won’t share until 2 days before the meeting. Take no offense at this – this, for some reason, is standard FDA procedure. (The FDA states they will provide the information at least two day before the meeting, which everybody is taking to mean it will happen two days prior. )

At Least Two Days Before the Meeting..We Will Know

Panel Makeup – The final makeup of the panel. We do know that the panel will be made up of persons from the Arthritis Advisory Committee and perhaps others but we’re not sure who. The FDA website states the committee is made up of 12 slots, six of which are vacant (including the Chair ). Of the six persons listed on the website one of them, Dr. Irwin Russell, is director of the Fibromyalgia Research and Consulting Clinical Research Section of South Texas. Another is an immunologist; none of the others, at first glance, have any indirect connections with CFS or FM.

Patient Advocate – the identity of the ‘Patient Advocate’, who presents the needs of the patient community to the panel will be listed.

Discussion Points/Questions – Hemispherx will want to rest up beforehand because the FDA may list a series of questions they want information on just two days before the epochal hearing takes place. Hemispherx may be cramming all the way up to the hearing..

Webcast Link – We’ll get the link for the webcast.

The information will be available here or maybe here; it’s not entirely clear from the notice..

STAR ALIGNING?

Ampligen has been under review of one sort or the other since the nineties, but after a surprisingly good year for Ampligen there is good reason to hope for a successful outcome. In July the FDA reversed a devastating 2009 decision requiring Hemispherx to produce new expensive studies which appeared to put Ampligen out of reach for good. With chronic fatigue syndrome gaining more prominence, though, and with the FDA being given a new mandate to give serious, underserved illnesses a foot up, Ampligen was back in the mix in 2012.

Key Legislation Provides An Opening

The 2012 FDA Safety and Innovation Act (FDASIA) passed in July appears to have played a key role in reversing Ampligen’s fate. The FDASIA encouraged the FDA to use a process called ‘accelerated approval’ which allows the Agency to conditionally approve drugs for ‘serious and life-threatening illnesses’ while drug companies worked on proving efficacy. This is a perfect mechanism for small drug companies like Hemispherx which would be allowed to market the drug and use the profits to fund further studies it couldn’t otherwise undertake.

Have the pieces come together for Ampligen and Hemispherx?

Coming just two days after the passage of FDASIA, the FDA turnaround on Ampligen might indicate the FDA is using the drug to make a statement regarding its willingness to follow FDASIA guidelines. Indeed, Sue Sutter, a noted business/pharmaceutical journalist suggested the FDA’s change of direction on Ampligen may have been directly influenced by the FDASIA.

More groundwork was laid on Sept 13th when FDA Deputy Director, Sandra Kweder, M.D. publicly stated on an ME/CFS Teleconference that the FDA considers ME/CFS to be a “serious and life threatening disorder”. An FDA notice for the meeting that specifically mentioned ‘accelerated approval’ and ‘unmet medical needs’ with regard to drugs for ME/CFS indicated that the FDA, again, was specifically drawing attention to FDASIA guidelines.

The FDA’s decision to hold an ME/CFS advocacy teleconference and use ME/CFS to produce it’s first Stakeholders Meeting for a disorder in decades next year also suggests a positive stance by the FDA. (One FDASIA provision calls for more patient involvement.) Sue Sutter called these efforts “a major step in the FDA’s efforts to raise the profile of CFS as a drug development target”.

Finally a Jan 2011 decision to consolidate, after being bumped around to six divisions, oversight of CFS treatments in the Division of Pulmonary, Allergy and Rheumatology Products, suggested the Agency was trying, finally, to get its arms around this disease and its challenges.

THE PLUS’S

The Drug

Ampligen out-performed a placebo in exercise trials

Patients on the drug were able to reduce their use of other medications, some of which can be harmful

Over 1,000 patients have been administered over 90,000 doses of the drug safely

Even long term use of Ampligen appears to be safe (ie does not cause disease)

Chronic fatigue syndrome is a relatively common disorder with no FDA approved drugs (and no other drugs in sight) which presents high economic costs to people who have it and to the nation as a whole

CDC figures suggest that chronic fatigue syndrome is functionally as disabling as multiple sclerosis and 10 times as common

Other disorders with few FDA approved drugs have been given more latitude with regard to drug efficacy at the FDA; ie if no other treatments are available the FDA is willing to relax its efficacy requirements.

FDASIA passage supports accelerated approval in cases where serious unmet needs are present and the drug is safe.

The MINUSES

The biggest hurdle Hemispherx has to deal with is the age and number of its studies. In 2009 the FDA wanted a brand spanking new study with lots of bells and whistles. The FDA relinquished that stance earlier this year but Hemispherx could be penalized for not being a billion dollar pharmaceutical company with resources to burn. Hemispherx’s re-analysis of its original data had Ampligen performing better. Will that be good enough?

Controversial Disease – with a poor definition. Will the disorders negatives trump its positives and the community’s needs? No federal agency has ever made the CFS communities needs a priority. Will the FDA be the first?

DECISION TIME

Taking Responsibility – The FDA rarely does not follow the decisions of its independent reviewers but the responsibility for the final decision is theirs. They, of course, contributed to Hemispherx’s dilemma by moving the drug around to six regulatory teams. Frustrated with these kind of bureaucratic bottlenecks and the slow pace of drug approvals, Congress acted in 2012 to make the FDA work more effectively for chronically ill people in the U.S.

It’s hard to see what the FDA has to lose by giving Ampligen Accelerated Approval status. They know the disorder is serious, they realize the community has huge unmet needs, they have proof of efficacy and most of all, they know the drug is safe.

POTENTIAL GAME CHANGER

Ampligen approval would change how ME/CFS is viewed leading to more respect and more funding

If approval occurs patients will get access to a drug that’s worked well for many, doctors will view ME/CFS as more of a treatable disorder and immune research will heat up. Future studies examining Ampligen’s effects could very well pave the way for a biomarker and uncover subsets.

FDA approval would also give pharmaceutical companies the message the FDA is serious about finding ways to get drugs to this community and that it will work with them where it can to do. A thumbs down could suggest the opposite.

Maybe the biggest change, though, would be a change in context for ME’/CFS. If you can change the context in which a thing occurs opportunities that were denied to it come naturally. An FDA approval would make this disorder more real as a disorder thus giving it more access to the opportunities other ‘real’ disorders have. The FDA does not approve drugs for figments of the imagination; it approves drugs for HIV, pneumonia and cancer. Ampligen approval would begin to thrust chronic fatigue syndrome into that realm and disorders like that get respect, they get interest and they get funding.